FUNCTIONAL ASSOCIATION OF CYCLOPHILIN-A WITH HIV-1 VIRIONS

CYCLOPHILINS are a family of proteins that bind the immunosuppressant cyclosporin A, possess peptidyl-prolyl cis-trans isomerase activity, a nd assist in the folding of proteins(1-6). Human cyclophilins A and B are host cell proteins that bind specifically to the HIV-1 Gag polypro tein p55(gag) in vitro(7). Here we report that viral particles formed by p55(gag), in contrast to particles formed by the Gag polyproteins o f other retroviruses, contain significant amounts of cyclophilin A. Se quences in the capsid domain of p55(gag) are both required and suffici ent for the virion-association of cyclophilin A. The association of cy clophilin A with HIV-1 virions was inhibited in a dose-dependent manne r by cyclosporin A as well as by SDZ NIM811 ([Melle-4] cyclosporin), a non-immunosuppressive analogue of cyclosporin A(8). Drug-induced redu ctions in virion-associated cyclophilin A levels were accompanied by r eductions in virion infectivity, indicating that the association is fu nctionally relevant. Moreover, SDZ NIM811 inhibited the replication of HIV-1 but was inactive against SIVIMAC, a primate immunodeficiency vi rus closely related to HIV-1, which does not incorporate cyclophilin A .